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X-linked hypophosphatemia (XLH) is the most common form of inheritable rickets. The disease is caused principally by PHEX mutations leading to increased concentrations of circulating intact FGF23, hence renal phosphate wasting, hypophosphatemia, and decreased circulating levels of 1,25(OH)2 vitamin D. The chronic hypophosphatemia leads to rickets and osteomalacia through a combination of mechanisms, including a lack of endochondral ossification and impaired mineralization. Imaging has a major role in determining the diagnosis of rickets and its cause, detecting complications as early as possible, and helping in treatment monitoring.

Context Enthesopathies are the determinant of a poor quality of life in adults with X-linked hypophosphatemia (XLH). Objective To describe the prevalence of patients with enthesopathies and to identify the risk factors of having enthesopathies. Methods Retrospective study in the French Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism between June 2011 and December 2020. Adult XLH patients with full body X-rays performed using the EOS® low-dose radiation system and clinical data collected from medical records. The main outcome measures were demographics, PHEX mutation, conventional treatment, and dental disease with the presence of enthesopathies. Results Of the 114 patients included (68% women, mean age 42.2 ± 14.3 years), PHEX mutation was found in 105 patients (94.6%), 86 (77.5%) had been treated during childhood. Enthesopathies (spine and/or pelvis) were present in 67% of the patients (n = 76). Patients with enthesopathies were significantly older (P = .001) and more frequently reported dental disease collected from medical records (P = .03). There was no correlation between the PHEX mutations and the presence of enthesopathies. Sixty-two patients had a radiographic dental examination in a reference center. Severe dental disease (number of missing teeth, number of teeth endodontically treated, alveolar bone loss, and proportion of patients with 5 abscesses or more) was significantly higher in patients with enthesopathies. Conclusion Adult XLH patients have a high prevalence of enthesopathies in symptomatic adults patients with XLH seen in a reference center. Age and severe dental disease were significantly associated with the presence of enthesopathies.

Summary X-linked hypophosphataemia (XLH) is a lifelong condition. Despite the mounting clinical evidence highlighting the long-term multi-organ sequelae of chronic phosphate wasting and consequent hypophosphatemia over the lifetime and the morbidities associated with adult age, XLH is still perceived as a paediatric disease. Introduction Children who have XLH need to transition from paediatric to adult healthcare as young adults. While there is general agreement that all affected children should be treated (if the administration and tolerability of therapy can be adequately monitored), there is a lack of consensus regarding therapy in adults. Methods To provide guidance in both diagnosis and treatment of adult XLH patients and promote better provision of care for this potentially underserved group of patients, we review the available clinical evidence and discuss the current challenges underlying the transition from childhood to adulthood care to develop appropriate management and follow-up patterns in adult XLH patients. Results and Conclusions Such a multi-systemic lifelong disease would demand that the multidisciplinary approach, successfully experienced in children, could be transitioned to adulthood care with an integration of specialized sub-disciplines to efficiently control musculoskeletal symptoms while optimizing patients’ QoL. Overall, it would be desirable that transition to adulthood care could be a responsibility shared by the paediatric and adult XLH teams. Pharmacological management should require an adequate balance between the benefits derived from the treatment itself with complicated and long-term monitoring and the potential risks, as they may differ across age strata.

Objective: To provide Italian expert opinion-based practical recommendations to improve the cooperation between clinicians and geneticists in order to optimize diagnostic flow and care of X-linked hypophosphatemia (XLH). Methods: A panel of four geneticists and four clinicians from Italian reference centers for the diagnosis and management of XLH met virtually, first to highlight the critical issues in patient care and then to identify and share proposals to improve the diagnostic and care path of XLH. Results: Critical issues emerged regarding the transfer of adequate clinical information from clinicians to geneticists, standardization and clarity of genetic reporting, and adequate interactions between clinicians and geneticists during patients’ follow-up. The necessary requirements for an appropriate request for evaluation of genetic variants and the need for a clear and clinically useful genetic report were agreed upon. Specifically designed template forms to be adopted with appropriate adjustments were defined and are here proposed for both the clinician’s request and the geneticist’s report. Conclusions: The expert group strongly believes that collaboration between clinicians and geneticists should be encouraged in XLH, not only in the diagnostic phase but also during a patient’s follow-up, in order to manage patients more comprehensively and effectively.

X-Linked Hypophosphatemia (XLH) is the most common cause of inherited hypophosphatemic rickets. Dental involvement, including spontaneous abscesses and/or fistulae, is an important part of the disease and has not been completely defined, especially in cohorts from developing countries. To describe oral health status in a cohort of Chilean patients with XLH and explore its correlation with biochemical presentation and treatment, we conducted a cross-sectional observational study of patients with PHEX mutation-confirmed XLH. All patients had an oral clinical exam, radiographic evaluation; clinical and biochemical data were obtained to determine their association with oral features. Twenty-six patients were included, 77% adults and 23% children. Most adults (89%) had past or current dental pulp pathology (abscesses and/or fistulae). Pulpal chamber enlargement and radiolucent apical lesions were common radiological features (94 and 74%, respectively). In children, abscess and/or fistulae were also common (33%). Caries index, which was determined by dmft/DMFT, was higher than the Chilean national average. Early and long-term therapy with phosphate and activated vitamin D was associated with lower carious index and attachment loss. XLH patients frequently present with high pulpal involvement and carious index. Conventional therapy was associated with lower carious index and attachment loss. These data highlight the importance of early and periodical dental care in order to prevent dental damage and assure a good quality of oral health for XLH patients.

We report the most comprehensive clinical and molecular characterization of XLH patients performed in Chile. We show high prevalence of musculoskeletal burden and pain, associated with significantly impaired physical capacity and quality of life, with many relevant complications presenting more frequently than previously reported in cohorts from developed countries. Our current understanding of the clinical presentation and natural history of X-linked hypophosphatemia (XLH) comes mainly from cohorts from developed countries, with limited data on the clinical and genetic abnormalities of XLH patients in South America. To describe the clinical, biochemical, and molecular presentation of patients with XLH in Chile. Patients with XLH referred by endocrinologist throughout Chile were included. Demographic data and clinical presentation were obtained from a clinical interview. Surveys were applied for quality of life (QoL), pain, and functionality. FGF23 was measured by ELISA, and genetic testing was performed. Imaging studies were conducted to assess skeletal and renal involvement. We included 26 patients, aged 2–64 years, from 17 unrelated Chilean families. All pediatric patients but only 40% of adults were receiving conventional therapy, while 65% of all patients had elevated alkaline phosphatase. All patients had mutations in PHEX, including 5 novel variants. Radiographic skeletal events (RSE) and enthesopathies in adults were frequent (34% and 85%, respectively). The duration of treatment was associated with fewer RSE (p < 0.05). Most adults reported pain and impaired QoL, and 50% had impaired physical capacity. The number of enthesopathies was associated with worse pain and stiffness scores (p < 0.05). Chilean patients with XLH have a high prevalence of musculoskeletal burden associated with pain and impaired physical capacity and QoL, especially in adults who were generally undertreated. These data identify a significant unmet need, inform our understanding of the current status of patients, and can guide care for XLH patients in similarly socioeconomically defined countries.

International audience; Rare diseases of phosphate/calcium metabolism correspond to a wide and heterogeneous spectrum of diseases. Recent knowledge in physiology and genetics has made it possible to better characterize them and to propose attractive therapeutic approaches based on the underlying pathophysiology. These diseases are often at the interface between nephrology and endocrinology. In this spirit of a multidisciplinary care, each specialty can bring its own critical point of view and its own specificities to improve patient care. The objective of this manuscript is to "read" with a nephrologist's point of view the main frameworks of diseases of phosphate/calcium metabolism, to illustrate the three crucial messages of nephro-protection sent to endocrinologists. First, calciuria must be interpreted both in absolute value (concentration hypercalciuria) and in ratio (flow hypercalciuria). Second, renal monitoring of therapies inducing hypercalciuria on kidneys with normal renal function (e.g. active vitamin D analogs or teriparatide) should be systematic. Last, hyperphosphatemia, often latent in hypoparathyroidism and pseudo-hypoparathyroidism, should be detected and at least benefit from dietary measures, in the context of Western diets rich in phosphate hidden in food additives.

Hypophosphatemic rickets (HR) is a genetic disorder with various types of inheritance. It results mainly from defects in factors that control mineral ion homeostasis such as 1,25(OH)2D (Calcitriol) and FGF23 (Fibroblast Growth Factor 23). The existing bibliography regarding orthodontic treatment in patients with hypophosphatemic rickets is extremely limited. The aim of this case report is to describe the orthodontic treatment of a 9-year old Caucasian female patient suffering from HR. The patient presented a healthy late mixed dentition and periodontium. She suffered from a mild Class III maxillary skeletal pattern. There was a bilateral posterior crossbite, short lingual frenulum, a right maxillary mesioposition with a Class II subdivision on this side and a moderate space deficiency in the dental arches. The disorder was controlled by medication. In specific, patient was taking 1.5mL of phosphate four times per day, 0.3mL of calcitriol twice per day and 50,000 IU of Vitamin D3 on a weekly basis. Given the Class III skeletal pattern, the medical condition and the absence of relevant bibliography, it was decided to perform maxillary expansion, facemask traction and orthodontic treatment with fixed appliances. By the end of treatment, Class I canine and molar relationships were achieved, overjet and overbite were corrected and space deficiency was addressed in both arches. PAR index was 27 at the beginning of treatment and became 2 by the end of treatment (92.5% correction). The aesthetic component of IOTN was 4 and changed to 1, while the dental component used to be 5i and became 2g. With regards to retention, upper and lower fixed retainers from canine to canine and upper and lower vacuum formed appliances were used. In conclusion, a patient with controlled HR was orthodontically treated in a successful way. Orthodontic therapy was performed in a minimally invasive manner. Thus, HR does not constitute a contraindication for orthodontic treatment, when the disorder is kept under control.

Background X-linked hypophosphatemia (XLH) represents the most common genetic form of rickets featuring profound hypophosphatemia with associated skeletal and non-skeletal manifestations. Early onset gait disturbances contribute strongly to the burden of disease. However, no study has comprehensively characterized naturally occurring gait deviations in pediatric patients with XLH. Research questions Can disease-specific gait deviations and potentially influencing factors be identified by gait analysis in non-surgically treated children with XLH? Methods Gait laboratory assessments of 12 pediatric patients with XLH without previous long bone surgery was retrospectively analyzed and compared to age-matched healthy controls. Radiologic and clinical parameters of XLH patients were correlated with kinematic gait variables and gait scores. Results Reduced external knee rotation and increased external hip orientation was ubiquitous in children with XLH. Increased lateral trunk lean, or “waddling gait”, occurred in five children and was associated with varus knee deformities. Overall, children with XLH showed a reduced Gait Deviation Index (GDI) compared to controls. Radiologic and gait analysis revealed complex combined frontal and torsional deformity of the lower limbs as a common feature in XLH. Higher Body Mass Index (BMI) was associated with both lateral trunk lean and impaired GDI. Significance Gait analysis is feasible to quantify gait deviations and lower limb deformities in pediatric patients with XLH. Specific gait characteristics including internal knee rotation and external hip rotation are common among patients with XLH and contribute to impaired gait scores. Our data suggest the use of gait and deformity data assessment as outcome parameters in future observational and interventional studies. Standardized assessment might contribute to targeted treatments to improve life quality in XLH patients.

X-linked hypophosphatemic rickets (XLH) is a skeletal disorder with spontaneous appearance of a periapical abscess in clinically healthy-like teeth a typical dental finding. A 1Y5M boy came to our clinic with spontaneous pain in the maxillary anterior region. Clinical examinations led to diagnosis of acute periapical periodontitis in the maxillary left primary central incisor, for which root canal treatment was performed. Thereafter, a pediatrician diagnosed XLH based on elevated ALP in a blood test at 1Y10M. We should have been suspected XLH in this case even with the absence of periapical abscess.

Purpose of review Perturbations in phosphate and vitamin D homeostasis impacts skeletal health in children and adults. Study of inherited and acquired hypophosphatemic syndromes led to the discovery of fibroblast growth factor 23 (FGF23) as a potent regulator of phosphate and vitamin D metabolism, and advanced our understanding of the pathophysiology of mineral and bone disorder in chronic kidney disease (CKD-MBD). Here, we review a recently approved therapy for patients with X-linked hypophosphatemia (XLH) using a novel anti-FGF23 antibody, burosumab, and discuss the implications of such targeted therapy in CKD. Recent findings In children and adults with XLH, burosumab treatment significantly increased renal tubular phosphate reabsorption and normalized serum phosphorus concentrations. Prolonged treatment with burosumab showed a favorable safety profile, improved healing of rickets in children, and fractures and pseudofractures in adults. FGF23 excess in CKD is independently associated with left ventricular hypertrophy and cardiovascular mortality. Research strategies to lower FGF23 in animal models of CKD are rapidly advancing and a question that remains to be answered is whether FGF23 blockade will offer a new targeted intervention for disordered mineral metabolism in CKD. Summary Findings from recently concluded clinical trials in adults and children with XLH provide evidence for improved skeletal health with burosumab therapy with normalization of phosphate and vitamin D metabolism. Targeted anti-FGF23 antibody treatment of XLH has emerged as a novel therapeutic strategy to treat an inherited disorder of FGF23 excess.

X-linked hypophosphatemia (XLH) is the most common inherited renal phosphate wasting disorder and is often misdiagnosed as vitamin D deficiency. This study aims to provide clinical and mutational characteristics of 65 XLH pediatric patients in southern China. In this work, a combination of DNA sequencing and qPCR analysis was used to study the PHEX gene in 80 pediatric patients diagnosed with hypophosphatemia. The clinical and laboratory data of confirmed 65 XLH patients were assessed and analyzed retrospectively. In 65 XLH patients from 61 families, 51 different variants in the PHEX gene were identified, including 23 previously reported variants and 28 novel variants. In this cohort of XLH patients, the c.1601C>T(p.Pro534Leu) variant appears more frequently. Fourteen uncommon XLH cases were described, including four boys with de novo mosaic variants, eight patients with large deletions and a pair of monozygotic twins. The clinical manifestations in this cohort are very similar to those previously reported. This study extends the mutational spectrum of the PHEX gene, which will contribute to accurate diagnosis. This study also suggests a supplementary qPCR or MLPA assay may be performed along with classical sequencing to confirm the gross insertion/deletion.

PURPOSE: X-linked hypophosphatemia (XLH) is a rare X-linked dominant metabolic bone disease, often diagnosed in childhood but causing increasing physical debilitation and pain in adulthood. Physical comorbidities of XLH in adulthood include pervasive and early-onset degenerative arthritis, mineralizing enthesophytes and osteophytes, osteomalacia and pseudofracture, dental abscesses, and hearing loss. METHODS: This mixed-methods analysis included physical findings, diagnostic imaging, occupational and physical therapy assessments, and semi-structured interviews by social work to understand the functional outcomes and lived experience of XLH in adulthood, through connections between qualitative data obtained by social work and occupational therapy with the quantitative findings from other disciplines. RESULTS: Three primary themes of chronic pain, fear of falling, and lack of credence given by health care providers emerged from qualitative data and could be correlated with physical findings from functional outcome assessments These concerns contrasted with resilience, adaption, and compensation demonstrated by participants. CONCLUSIONS: While new treatments may ease the burden of disease for adults with XLH, further research, increased provider awareness and education, and further development of standards of care are needed to promote accurate and adequate assessment and intervention for adults with XLH.

X-linked hypophosphatemia (XLH) is the most common form of inherited hypophosphatemic rickets. Phosphate wasting results in weak, soft and deformed bones, impaired growth, and affected mobility. It is mainly caused by a loss of function mutation in PHEX gene that leads to elevated fibroblast growth factor-23 which mediates the phosphate wasting. During the 58th annual meeting of the European Society of Pediatric Endocrinology (ESPE) held in Vienna between September 19, 2019 and 21, 2019, nearly 100 free communications and a dedicated symposium focused on XLH. The authors attended the conference and wished to share its highlights pertaining to XLH and burosumab therapy to extend the benefit to other professionals who did not attend.

Background/aim X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to a link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH. Patients/methods We studied 172 XLH-children 5–20 years of age (113 girls/59 boys). Anthropometric parameters (weight, height, and BMI) were collected at birth and during follow-up at mean ages of 5.3, 8.2, 11.3, and 15.9 years (groups 1, 2, 3, and 4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25–30 or ≥30 kg/m2, respectively). Results In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4, 28.7, 27.5, and 36.7% in groups 1, 2, 3, and 4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3 ± 4.4 vs 23.8 ± 3.8 vs 25.2 ± 4.5 kg/m2, for subjects with treatment duration of 10 years, respectively, P for trend = 0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF. Conclusion One out of three of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight or obesity in comparison to general population. Both the lack of XLH family history and the duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children, and later in adults, with XLH.

Description, A new therapeutic approach for the treatment of a skeletal disorder with AAVs bypasses bone resistance to gene transfer., Adeno-associated virus (AAV) vectors are a well-established gene transfer approach for rare genetic diseases. Nonetheless, some tissues, such as bone, remain refractory to AAV. X-linked hypophosphatemia (XLH) is a rare skeletal disorder associated with increased levels of fibroblast growth factor 23 (FGF23), resulting in skeletal deformities and short stature. The conventional treatment for XLH, lifelong phosphate and active vitamin D analogs supplementation, partially improves quality of life and is associated with severe long-term side effects. Recently, a monoclonal antibody against FGF23 has been approved for XLH but remains a high-cost lifelong therapy. We developed a liver-targeting AAV vector to inhibit FGF23 signaling. We showed that hepatic expression of the C-terminal tail of FGF23 corrected skeletal manifestations and osteomalacia in a XLH mouse model. Our data provide proof of concept for AAV gene transfer to treat XLH, a prototypical bone disease, further expanding the use of this modality to treat skeletal disorders.

X-linked hypophosphatemia (XLH) is a rare genetic phosphate disorder caused mainly by PHEX mutations. Unlike for children, knowledge of the disease's manifestations in adults is limited. Musculoskeletal symptoms are the main feature of the disease in young adults associated with a heavy burden on patients' life. They include fractures and pseudofractures, pain, joint stiffness, osteoarthritis, enthesopathies, and muscle weakness, eventually leading to impaired quality of life. Conventional treatment with phosphate supplements and vitamin D analogs is indicated in symptomatic patients. Appropriate rehabilitation is also a key to the management of the disease to improve physical function and decrease pain, stiffness, and fatigue. Regarding the incidence and consequences of musculoskeletal features in XLH, all patients should be assessed by a bone disease specialist and, if necessary, managed by a multidisciplinary team.

X-linked hypophosphatemia (XLH) is due to mutations in the PHEX gene leading to unregulated production of FGF23 and uncontrollable hypophosphatemia. XLH is characterized in children by rickets, short stature, waddling gait, and leg bowing of variable morphology and severity. Phosphate supplements and oral vitamin D analogs partially or, in some cases, fully restore the limb straightness. XLH patients may also be affected by premature, complete, or partial ossification of sutures between cranial bone, which could eventually result in cranial dysmorphia, decreased intracranial volume, and secondary abnormally high intracranial pressure with a cerebral compression. Our goal is to address the criteria and the management of the skeletal complications associated with XLH, mainly orthopedic and neurosurgical care, and reflect on decision-making and follow-up complexities.

X-linked hypophosphatemia (XLH) is a hereditary musculoskeletal disorder caused by loss-of-function mutations in the PHEX gene. In XLH, increased circulating fibroblast growth factor 23 (FGF23) levels cause renal phosphate wasting and low concentrations of 1,25-dihydroxyvitamin D, leading to an early clinical manifestation of rickets. Importantly, hearing loss is commonly observed in XLH patients. We present here data from two XLH patients with marked conductive hearing loss. To decipher the underlying pathophysiology of hearing loss in XLH, we utilized the Hyp mouse model of XLH and measured auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) to functionally assess hearing. As evidenced by the increased ABR/DPOAE threshold shifts in the mid-frequency range, these measurements indicated a predominantly conductive hearing loss in Hyp mice compared to wild-type (WT) mice. Therefore, we carried out an in-depth histomorphometric and scanning electron microscopic analysis of the auditory ossicles. Quantitative backscattered electron imaging (qBEI) indicated a severe hypomineralization of the ossicles in Hyp mice, evidenced by lower calcium content (CaMean) and higher void volume (ie, porosity) compared to WT mice. Histologically, voids correlated with unmineralized bone (ie, osteoid), and the osteoid volume per bone volume (OV/BV) was markedly higher in Hyp mice than WT mice. The density of osteocyte lacunae was lower in Hyp mice than in WT mice, whereas osteocyte lacunae were enlarged. Taken together, our findings highlight the importance of ossicular mineralization for hearing conduction and point toward the potential benefit of improving mineralization to prevent hearing loss in XLH. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

X-linked hypophosphatemia (XLH) is a rare inheritable disorder of phosphate handling due to loss of function mutations of the PHEX gene, associated with increased production of FGF23 and impaired bone mineralization. In children, the disease's most common manifestations are bowing deformities of the lower limbs, short stature, and spontaneous dental abscesses. In adults, these are osteomalacia, insufficiency fractures, and enthesopathies associated with bone and joint pain. The XLH patient's journey with the disease may be difficult, reflecting concerns and experiences globally common to all patients with rare genetic diseases. Delays in diagnosis often preclude an optimal treatment outcome. Under-treatment is common as treating physicians, particularly those not familiar with the disease, tend to err on the side of caution, often choosing safety over efficacy. Physical abnormalities, pain, diminished function, and impaired mobility tend not only to isolate the XLH patient from his peers but also to have a significant psychological effect, eventually leading to significant impairment in quality of life. Significant advances in understanding the pathophysiology of XLH, the availability of a very comprehensive Evidence-based Guideline for the diagnosis and management of XLH, and the successful development of an effective and safe disease-specific novel therapy for XLH, have paved the way for a significant improvement in the management of this rare disorder of phosphate metabolism, heralding a significant improvement in the disease's outcome measures. Additional data from longterm observational studies and randomized controlled trials are eagerly awaited to consolidate these promising developments in the field of this rare disease. (C) 2021 The Authors. Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate-wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades-old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (

Context We characterized linear growth in infants and children with X-linked hypophosphatemia (XLH). Objective Provide linear growth curves for children with XLH from birth to early adolescence. Design Data from 4 prior studies of XLH were pooled to construct growth curves. UX023-CL002 was an observational, retrospective chart review. Pretreatment data were collected from 3 interventional trials: two phase 2 trials (UX023-CL201, UX023-CL205) and a phase 3 trial (UX023-CL301). Setting Medical centers with expertise in treating XLH. Patients Children with XLH, 1-14 years of age. Intervention None. Main Outcome Measure Height-for-age linear growth curves, including values for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for children with XLH compared to population norms. Results A total of 228 patients (132 girls, 96 boys) with 2381 height measurements were included. Nearly all subjects (> 99%) reported prior management with supplementation therapy. Compared to the Center for Disease Control and Prevention growth curves, boys at age 3 months, 6 months, 9 months, 1 year, and 2 years had median height percentiles of 46%, 37%, 26%, 18%, and 5%, respectively; for girls the median height percentiles were 52%, 37%, 25%, 18%, and 7%, respectively. Annual growth in children with XLH fell below that of healthy children near 1 year of age and progressively declined during early childhood, with all median height percentiles < 8% between 2 and 12 years old. Conclusion Children with XLH show decreased height gain by 1 year of age and remain below population norms thereafter. These data will help evaluate therapeutic interventions on linear growth for pediatric XLH.

Background: X-linked hypophosphatemia rickets (XLH) is a genetic disorder of phosphate wasting that causes the majority of inherited hypophosphatemic rickets. The disease is caused by mutations in the phosphate-regulating endopeptidase gene (PHEX). All types of mutations have been detected in the PHEX gene. There is no clear preference for the position and the type of mutation.Methods: In this study, we performed DNA sequencing and ex vivo splicing analysis to study the PHEX gene in ten sporadic patients and six core families with XLH. Results: A total of 25 patients were studied. Fifteen different mutations were detected in these patients, including five missense mutations, five splicing mutations, two nonsense mutations, two small deletions, and one small insertion. Five mutations were not previously reported. We also characterized the splicing mutations identified in our study, which consisted of exon skipping and activation of new splice sites in an exon or intron. Most of the observed changes resulted in a frameshift of the PHEX open reading frame.Conclusions: The genetic etiology in patients with XLH were successfully identified. This study expands the mutation database of the PHEX gene. We also explored the pathogenesis of XLH caused by splice site mutations. These results will contribute to the diagnosis of XLH and the pathogenicity analysis of mutations in patients.

Background: X-linked hypophosphatemia (XLH) is the most frequent form of hypophosphatemic rickets and is caused by mutations in the PHEX gene. We analyzed genotype-phenotype correlations in XLH patients with proven PHEX mutations.Methods:PHEX mutations were detected in 55 out of 81 patients who clinically presented with hypophosphatemic rickets. The patients were grouped into nontruncating (n = 9) and truncating (n = 46) mutation groups; their initial presentation as well as long-term clinical findings were evaluated according to these groups.Results: Initial findings, including presenting symptoms, onset age, height standard deviation scores (SDS), and laboratory tests, including serum phosphate level and tubular resorption of phosphate, were not significantly different between the two groups (onset age: nontruncating mutation group, 2.0 years, truncating mutation group, 2.2 years; height SDS: nontruncating mutation group, −1.9, truncating mutation group, −1.7; serum phosphate: nontruncating mutation group, 2.5 mg/dL, truncating mutation group, 2.6 mg/dL). However, at their last follow-up, the serum phosphate level was significantly lower in patients with truncating mutations (nontruncating mutation group: 3.2 mg/dl, truncating mutation group: 2.3 mg/dl; P = 0.006). Additionally, 62.5% of patients with truncating mutations developed nephrocalcinosis at their last follow-up, while none of the patients with nontruncating mutations developed nephrocalcinosis (P = 0.015). Orthopedic surgery due to bony deformations was performed significantly more often in patients with truncating mutations (52.3 vs. 10.0%, P = 0.019).Conclusion: Although considerable inconsistency exists regarding the correlation of truncating mutations and their disease phenotype in several other studies, we cautiously suggest that there would be genotype-phenotype correlation in some aspects of disease manifestation after long-term follow-up. This information can be used when consulting patients with confirmed XLH regarding their disease prognosis.

X-linked hypophosphatemia (XLH) is an inherited disorder characterized by low levels of phosphate in the blood. Phosphate levels are low because phosphate is abnormally processed in the kidneys, which causes urinary phosphate wasting and leads to rickets in the young patients and osteomalacia in adults in addition to several other complications thereof. A 3-day conference was hosted by the Rare Diseases Unit of the Bicetre Paris Sud Hospital on July 4–6, 2019. Presentations covered the subject in a comprehensive manner spanning physiology, clinical presentations, disease burden, and the latest in the management of the XLH and its musculoskeletal, neurosurgical, obstetric, and other complications in both children and adults. Several illustrative and challenging cases were presented and discussed. The authors attended the event and would like to present a personal perspective to highlight the proceeding of the conference to extend the benefit to others who did not attend it.

Context X-linked hypophosphatemia (XLH) is characterized by excess fibroblast growth factor 23 (FGF23), hypophosphatemia, skeletal abnormalities, and growth impairment. We aimed to understand the burden of disease of XLH across the lifespan. Methods Responses were collected from adults with XLH and parents/caregivers of a child with XLH in an online survey, including multiple-choice and open-ended questions on demographics, disease manifestations, treatment history, assistive device use, and age-specific patient-reported outcomes (PROs). Results Data were collected from 232 adults with XLH (mean age, 45.6 years; 76% female) and 90 parents/caregivers of a child with XLH (mean age, 9.1 years; 56% female). Mean age recalled for symptom onset was 3.2 years for adults and 1.3 years for children. When surveyed, nearly all children (99%) and 64% of adults were receiving oral phosphate, active vitamin D, or both. Prior participation in a trial investigating burosumab, a fully human monoclonal antibody against FGF23, was reported in 3% of children and 10% of adults; of these respondents, only one child reported current treatment with burosumab at the time of the survey. Both children and adults reported typical features of XLH, including abnormal gait (84% and 86%, respectively), bowing of the tibia/fibula (72% and 77%), and short stature (80% and 86%). Nearly all adults (97%) and children (80%) reported bone or joint pain/stiffness. Adults reported a history of fractures (n/N = 102/232; 44%), with a mean (SD) age at first fracture of 26 (16) years. Adults reported osteophytes (46%), enthesopathy (27%), and spinal stenosis (19%). Mean scores for PROs evaluating pain, stiffness, and physical function were worse than population norms. Analgesics were taken at least once a week by 67% of adults. Conclusions Despite the common use of oral phosphate and active vitamin D established in the 1980s, children with XLH demonstrate a substantial disease burden, including pain and impaired physical functioning that persists, as demonstrated by similar responses reported in adults with XLH.

Background X-linked hypophosphatemia is associated with a range of dental problems, many of which may result in early loss of the dentition. Most patients, but especially young adults, are likely to desire fixed prosthodontic replacements, and dental implants may be the preferred solution in many cases. The use of dental implants to rehabilitate this patient group has not been widely studied with the literature limited to a small number of case reports with limited follow-up. Case presentation This case report describes the dental journey of a young adult with X-linked hypophosphatemia, his eventual tooth loss and rehabilitation with multiple dental implants. Over 10 years’ follow-up of three of the fixtures is presented. Conclusions This case report shows a common presentation and progression of a patient with X-linked hypophosphatemia and will hopefully provide further positive evidence for the clinician to rely on when considering dental implant based treatments for such patients.

Aspects of bone remodeling have only been scarcely studied in X-linked hypophosphatemia (XLH). In this cross-sectional controlled study, we assessed biochemical indices of bone remodeling and sclerostin in 27 adult patients (median age 47 [range 24-79] years, 19 women, 8 men) with XLH matched with 81 healthy control subjects (1:3) with respect to age-, sex-, and menopausal status. Markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen, CTX) and formation (N-terminal propeptide of type 1 procollagen, P1NP) were higher in XLH patients compared to controls (median [IQR] 810 [500-1340] vs 485 [265-715] ng/l and 90 [57-136] vs 49 [39-65] ug/l, respectively, both p

To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). Multicentre prospective clinical study on pediatric patients included in the RenalTube database ( www.renaltube.com ) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study’s protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. Twenty-four patients (17 females, from 1 to 17 years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60 mg/dl and 58.3 ± 26.8 pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45 pg/ml (normal

X-linked hypophosphatemia (XLH) is associated with a pervasive, severe degenerative osteoarthritis. We conducted a retrospective chart review/patient survey using the Knee or Hip Osteoarthritis Outcome Score Physical Function Short Form. Fourteen total knee arthroplasties and 7 total hip arthroplasties among 11 patients were included. The mean KOOS-PS score was 31.4 ± 9.7 with a mean follow up of 6.9 years. Mean HOOS-PS score was 14.8 ± 12.9 at a mean follow up of 7.6 years. One knee failed due to aseptic loosening and one hip was revised due to polyethylene wear. In conclusion, total joint arthroplasty is beneficial in XLH.

Background. X-linked hypophosphatemia (XLH) is a rare, hereditary, and lifelong phosphate wasting disorder characterized by rickets in childhood and impaired teeth mineralization. In the oral cavity, spontaneous abscesses can often occur without any clinical signs of alteration of the causal tooth. The objective of our study was to evaluate the oral care pathway and the oral health-related quality of life (OHRQoL) of patients followed in an expert oral medicine department located within a Parisian hospital and working in close collaboration with an endocrinology department expert in this pathology. Methods. This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. Results. Twenty-one patients were included in the study. The topics brought up exceeded the initial objectives as the patients mostly addressed the alteration of their oral and general quality of life; a very chaotic oral health care pathway with oral health professionals not aware of their pathology; consequences on their social, professional, and school integration; access to care complicated by financial factors. Patients declared the importance of having a multidisciplinary team around them, including medical and dental professionals.Conclusions. The variety of manifestations in patients with XLH necessitates a high coordination of multidisciplinary patient care to optimize quality of life and reduce disease burden. Oral health care pathways are very chaotic for patients who have difficulty finding professionals with sufficient knowledge of the disease. OHRQoL is therefore diminished. This situation improves when patients enter a coordinated care network.

X-linked hypophosphatemia (XLH) is caused by inactivating mutations in thephosphate-regulating endopeptidase homolog, X-linked(PHEX) gene, resulting in an excess of circulating intact fibroblast growth factor-23 (iFGF-23) and a waste of renal phosphate. In the present study, we retrospectively reviewed the clinical and molecular features of 153 Chinese patients, representing 87 familial and 66 sporadic cases with XLH. A total of 153 patients with XLH presented with signs or symptoms at a median age of 18.0 months (range, 9.0 months–26.0 years). Lower-limb deformity was the most frequent clinical manifestation, accounting for 79.1% (121/153). Biochemical screening showed increased serum levels of iFGF23 in patients with XLH, with a wide variation ranging from 14.39 to 730.70 pg/ml. Median values of serum iFGF23 in pediatric and adult patients were 94.87 pg/ml (interquartile range: 74.27–151.86 pg/ml) and 72.82 pg/ml (interquartile range: 39.42–136.00 pg/ml), respectively. Although no difference in circulating iFGF23 levels between these two groups was observed (P= 0.062), the proportion of patients with high levels of circulating iFGF23 (>42.2 pg/ml) was greater in the pediatric group than in the adult group (P= 0.026). Eighty-eight different mutations in 153 patients were identified, with 27 (30.7%) being novel. iFGF23 levels and severity of the disease did not correlate significantly with truncating and non-truncating mutations or N-terminal and C-terminalPHEXmutations. This study provides a comprehensive description of the clinical profiles, circulating levels of iFGF23 and gene mutation features of patients with XLH, further enriching the genotypic spectrum of the diseases. The findings show no evident correlation of circulating iFGF23 levels with the age or disease severity in patients with XLH.

The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

There is an error in the Conflict of Interest statement. The correct statement is “ML has received lecture and consultancy fees from Alexion, Amgen, Kyowa Kirin, Menarini, Sandoz, Takeda, UCB and Will-Pharma. JS has received lecture, consultancy fees, and conference support from Kyowa Kirin, Alexion, Eli-Lily, Ferring, Ipsen, Menarini, Novo Nordisk, Pfizer, Sandoz, and Siemens Healthcare. DT has received conference support from Novo Nordisk. NG, JLa, and KH have received consultancy fees from Kyowa Kirin. EB has received conference support from Novo Nordisk and Pfizer. CH has received conference support from Novo Nordisk and Ferring. EC has received consultancy fees from bioMérieux, Diasorin, Fujirebio, IDS, and Menarini. PH is an employee of GlaxoSmithKline but participates in his own capacity. J-FK has received consultancy fees and conference support from Heel Belgium, Sanofi, and TRB Chemedica. KW has received conference support from Alexion, Ferring, Kyowa Kirin and Novo Nordisk. CV has received conference support from Boehringer Ingelheim. GM has received consultancy fees from Alexion, Biomarin, Kyowa Kirin, and Pfizer. EL has received consultancy fees and travel support from Kyowa Kirin, Chiesi, and Recordati. JV has received conference support and consultancy fees from Alexion, Bellco, Ferring, Medtronic, and Kyowa Kirin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. There should be a change to Treatment section. A 0.4 mg/kg bodyweight dose is mentioned, whereas the most recently approved dose is a 0.8 mg/kg bodyweight dose. In the subsection “Burosumab” in the fifth paragraph, the first sentence should read as follows: The EMA-approved dose in children is a 2-weekly s.c. injection starting 0.8 mg/kg bodyweight, increased with 0.4 mg/kg dose increments (max. 2.0 mg/kg, cap at 90 mg dose) to achieve fasting plasma phosphate concentrations in the lownormal range for age. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

A 7-year-old girl without a significant previous medical history was diagnosed with X-linked hypophosphatemic rickets (XLHR) due to a rare, most likely pathogenic, PHEX gene variant after a 4-year delayed diagnosis due to mild clinical presentation. At 2 years of age, her intoeing and femoral bowing were attributed to physiologic bowing and borderline vitamin D sufficiency, despite phosphorus not being measured. Hypophosphatemia was eventually detected after incomplete improvement of bowing and leg length discrepancy with suboptimal linear growth. This rare PHEX variant (c.1949T>C, p.Leu650Pro) further supported the clinical diagnosis of XLHR. Treatment with burosumab (an anti-FGF23 monoclonal antibody) normalised phosphorus and alkaline phosphatase levels and improved her bowing. The diverse phenotypic presentation of this variant can result in delayed diagnosis and highlights the importance of prompt assessment of phosphorus levels in patients with skeletal deformities to ensure timely recognition and treatment.

Context Patients with X-linked hypophosphatemia (XLH) experience multiple musculoskeletal manifestations throughout adulthood. Objective To describe the burden of musculoskeletal features and associated surgeries across the lifespan of adults with XLH. Methods Three groups of adults were analyzed: subjects of a clinical trial, participants in an online survey, and a subgroup of the online survey participants considered comparable to the clinical trial subjects (according to Brief Pain Inventory worst pain scores of ≥ 4). In each group, the adults were categorized by age: 18-29, 30-39, 40-49, 50-59, and ≥ 60 years. Rates of 5 prespecified musculoskeletal features and associated surgeries were investigated across these age bands for the 3 groups. Results Data from 336 adults were analyzed. In all 3 groups, 43% to 47% had a history of fracture, with the proportions increasing with age. The overall prevalence of osteoarthritis was > 50% in all 3 groups, with a rate of 23% to 37% in the 18- to 29-year-old group, and increasing with age. Similar patterns were observed for osteophytes and enthesopathy. Hip and knee arthroplasty was reported even in adults in their 30s. Spinal stenosis was present at a low prevalence, increasing with age. The proportion of adults with ≥ 2 musculoskeletal features was 59.1%, 55.0%, and 61.3% in the clinical trial group, survey group, and survey pain subgroup, respectively. Conclusion This analysis confirmed high rates of multiple musculoskeletal features beginning as early as age 20 years among adults with XLH and gradually accumulating with age.

The authors present a stereotypical case presentation of x-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact Fibroblast Growth Factor 23 (FGF23) which lead to i) low serum phosphate levels, ii) increased fractional excretion of phosphorus, and iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in XLH patients is due to chronic hypophosphatemia. Additionally, XLH patients experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration’s (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

Background. X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, and lifelong phosphate wasting disorder characterized by pathological elevations in fibroblast growth factor (FGF) 23 serum concentration and activity. In the oral cavity, spontaneous abscesses can occur often without any clinical signs of alteration of the causal tooth. The objective of our study was to evaluate the readability of the oral care pathway and the oral quality of life of patients followed in an expert oral medicine department located within a Parisian hospital and working in close collaboration with an endocrinology department expert in this pathology. Methods. This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. Results. Twenty-one patients were included in the study, with an average age of 28 years. The topics discussed exceeded the initial objectives as the patients largely addressed the alteration of their oral and general quality of life, a very chaotic oral health care pathway with oral health professionals not aware of their pathology, consequences on their social, professional, and school integration and access to care complicated by financial factors. Patients reported the importance of having a multidisciplinary team around them, including medical and dental professionals.Conclusions. The variety of manifestations in patients with XLH necessitates a high coordination of multidisciplinary patient care to optimize quality of life and reduce disease burden. Education of oral health professionals on this disease is essential to enable patients to receive the best possible care as early as possible.

In this report of otological involvement in XLH patients, 23% of them presented hearing loss. Patients with hearing loss had higher prevalence of tinnitus and lower serum phosphate compared to patients without hearing loss. Otologic involvement was not significantly associated to the severity of other XLH manifestations. Special attention should be given to children, considering that none of them reported symptoms of hearing loss, but up to one third of them had audiometric abnormalities. An active search strategy of otological involvement is needed in patients with XLH.

Purpose To examine the MRI diagnostic performance in the assessment of therapeutic response to burosumab in children with X-linked hypophosphatemia (XLH). Design Prospective longitudinal open cohort. Patients Seventeen children with XLH, average age of 10.2 ± 2.7 years, had a knee MRI at baseline and after 1 year of burosumab. Intervention Children received burosumab at an average dose of 1.4 ± 0.5 mg/kg during 1 year for the treatment of severe rickets (the target serum phosphate ≥ 1.2 mmol/L (≥3.7 mg/dL). The primary endpoint was the change from baseline to 12 months in rachitic lesions on knee MRI. Secondary endpoints were changes in biochemical parameters of phosphate and alkaline phosphatase (ALP). Results One year of treatment with burosumab significantly reduced radiological disease activity on knee MRI (by 44 ± 29% in the transverse extent of widening) which was accompanied by a significant reduction in biochemical activity, namely in serum ALP activity, by 28 ± 17%. Additionally, MRI parameters after 1 year of treatment with burosumab (the maximum width of medial physis at 12 months and the change from baseline in the maximum width of lateral physis) were associated with ALP activity at 12 months. Conclusion We suggest that MRI is a valuable and quantitative tool to evaluate the therapeutic response to burosumab. MRI could be an excellent alternative to standard bone radiographs for evaluation of the rachitic lesions in a clinical setting avoiding repeated exposition to ionizing radiation.

In children and adolescents, distinguishing tumor-induced rickets/osteomalacia (TIR/O) from hereditary hypophosphatemic rickets/osteomalacia (HR/O) is a medical challenge. We retrospectively studied 10 Chinese children and adolescents with TIR/O who underwent surgery at a mean age of 17.4 ± 2.1 years and compared their characteristics to 24 age- and sex-matched patients with X-linked hypophosphatemia (XLH). Positive family history of HR/O and dental problems, such as enamel hypoplasia and dental abscess, were reported in 8 (33.3%) and 5 (20.8%) patients with XLX, respectively, but not in patients with TIR/O. In addition, in comparison with XLH patients, TIR/O patients had an older disease onset age (150 versus 24 months, p